The prostaglandins are an extremely important, biologically active class of C-20 unsaturated hydroxy-acids discovered first in the 1930s by Goldblatt and Von Euler in extracts of human seminal fluid and sheep vesicular glands. Due to the difficulties in isolating and determining the structures of milligram quantities of these compounds, it was not until the 1960s that their structures were determined. By then, the extreme physiological activity of these compounds was evident, and the desire for larger amounts of these valuable compounds for biological testing stimulated organic chemists to tackle the formidable problem of synthesizing these highly functionalized molecules. Within a few short years, a number of total syntheses of all of the primary prostaglandins had appeared led by the work of Professor E.J. Corey and his group at Harvard (see U. Axen, J.E. Pike and W. P. Schneider in "The Total Synthesis of Natural Products", Vol. 1, J. ApSimon, Ed., Wiley-Interscience, New York, 1973, pp. 81-142, which is incorporated herein by reference).
With the ready availability of these compounds for the first time, extensive biological testing ensued. Prostaglandins have subsequently been found to have pronounced effects on the cardiovascular and renal systems; the respiratory tract; the eye, skin, lungs, and bone; and the reproductive organs. Within the cardiovascular system alone, they apparently play a central role in regulating blood platelet aggregation, blood pressure and flow, cardiac output, heart rate, and vascular activity. While prostaglandins appear to have pharmacological potential in the treatment of asthma, nasal congestion, stomach ulcers, inflammation, hypertension, thrombosis, etc., considerable attention so far has focused on their possible use in the induction of labor, termination of pregnancy, and possible utility in contraception.
To date, the major drawbacks to clinical application of the prostaglandins have been the very broad range of physiological activity prevalent in these compounds and their brief duration of action due to rapid metabolic deactivation. The desire for longer lasting drugs exhibiting much more specific activity has recently produced a number of very interesting analogs of prostaglandins and many structure-activity studies have resulted. The interesting synthetic work of J. Fried at Chicago on oxa analogs, and recent synthesis of 8-, 12-, and 15-methyl prostaglandins which are blocked from undergoing the usual metabolic deactivation should be noted in this regard. Fried, et al., Ann. N.Y. Acad. Sci., 180, 38 (1971), incorporated herein by reference. Some of these synthetic analogs will hopefully find clinical application.
Tremendous potential also exists in the development of prostaglandin antagonists and reagents which will inhibit prostaglandin bio-synthesis and metabolism. At present, only a few prostaglandin antagonists are known. The best known and most studied are the dibenzoxazepine derivatives, especially SC-19220, phosphorylated polymers of phloretin, especially polyphloretin phosphate; and oxa- and thia-prostaglandin analogs, particularly 7-oxa-13-prostanoic acid. Considerable recent interest has also developed in potential antagonists of prostaglandin biosynthesis. In fact, it has been suggested that the biological activity of anti-inflammatory, analgesic and antipyretic drugs can be explained by the fact that they inhibit the biosynthesis of prostaglandins. It is, therefore, possible that the synthesis of specific inhibitors of prostaglandin biosynthesis and prostaglandin receptor antagonists could produce some clinically useful drugs.
For these reasons, there has been considerable work of late on the biosynthetic pathways involved in the formation of prostaglandins.
Although the natural prostaglandins show promise as potential drugs, there are a number of problems. For instance, they are metabolized very rapidly within the body. Studies on humans show that prostaglandin E.sub.2, a smooth muscle contractor that is used to induce labor or terminate pregnancy, when given intravenously at 96.degree. is deactivated in the first 90 seconds after administration. A more perplexing problem is the lack of tissue specificity of the prostaglandins. Prostaglandin E.sub.2, in addition to causing uterine smooth muscle to contract to induce labor, causes gastrointestinal smooth muscle to contract, leading to cramps and diarrhea. This same compound, when aspirated into the nostrils, immediately dilates the bronchi and alleviates asthmatic attack, but at the same time, it irritates the mucous lining of the throat, causing pain and coughing.
The therapeutic potential of the prostaglandins and the lack of an abundant natural source of these compounds has led to a number of laboratory investigations to provide a total synthesis as a method of obtaining them. In addition, because of their lack of specificity in inducing pharmacological activity, it has been thought desirable to develop significant analogs of prostaglandin compounds which would be more stable than natural prostaglandins, and which would have more specificity in providing pharmacological activity.
It is an object of this invention to provide prostaglandin-like compounds which are convenient synthetic precursors for desired prostaglandins, which are thermally stable and can be prepared at good yield levels.
Yet another object of this invention is to provide prostaglandin precursors which can selectively be reacted to provide either exo or endo analogs of prostaglandins.
Yet another object of this invention is to provide a convenient and simple synthesis route for preparing precursors of prostaglandin compounds by adding an alkyl (acetoxymercurio) carboxylate to norbornene or related bicyclic olefins in the presence of a palladium salt and a 1-alken-3-one in order to produce a ketoester of a bicycloheptane.